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Marwan Shinawi, MD
Department of Pediatrics, Division of Genetics and Genomic Medicine
Washington University School of Medicine
St. Louis, MO
Shinawi_M@kids.wustl.edu

Summary

Disease characteristics. Autism comprises a clinically heterogeneous group of disorders – collectively referred to as “autism spectrum disorders” (ASD) – that share common features of impaired social relationships, impaired language and communication, and repetitive behaviors or a narrow range of interests. For most children with autism, symptoms develop gradually, although approximately 30% have a "regressive" onset usually between ages 18 and 24 months. About 50%-70% of children with autism are identified as intellectually disabled by nonverbal IQ testing and approximately 25% develop seizures. Autism can be considered complex (i.e., presence of dysmorphic features and/or microcephaly) or essential (i.e., absence of physical abnormalities and microcephaly). About 25% of children who fit the diagnostic criteria for ASD at age two to three years subsequently begin to talk and communicate, and by age six to seven years blend to varying degrees into the regular school population. The remaining 75% have lifelong disability requiring intensive parental, school, and social support.

Diagnosis/testing. The behavioral criteria presented in the American Psychiatric Association Manual of Psychiatric Diseases, 4th edition (DSM-IV) remain the standard for making an autism diagnosis in the US. Currently, three subgroups (autistic disorder, Asperger syndrome, and PDD-NOS) are recognized. To qualify for a diagnosis of autistic disorder (i.e., classic autism), a child must have shown abnormalities in social interaction and language used for social communication or symbolic/imaginative play and either stereotypic motor mannerisms or restricted patterns of interest before age three years. If the child does not meet criteria for autistic disorder, he or she may be given a diagnosis of Asperger syndrome (AS) or pervasive developmental disorder-not otherwise specified (PDD-NOS), the other two disorders included in ASD. Autism has many etiologies, a concept that was widely embraced following the discovery of the molecular basis of Rett syndrome in 2006. Since then autism has been documented in hundreds of neurologically based syndromes with multiple causes, outcomes, and treatment responses. Currently, an etiology can be identified for between 15% and 20% of individuals with autism; in the others the cause remains unknown.

Management. Treatment of manifestations: Management of autism involves educational, behavioral, and medical therapies to promote conversational language and social interactions while mitigating repetitive self-stimulatory behaviors, tantrums, aggression, and self-injurious behaviors. The mainstay of therapy is early individualized intensive training either in the school or home, where the environment must be predictable with planned transitions between activities and venues. Visual supports are helpful in promoting language acquisition. The Visually Cued Instruction and Schedules program uses graphic clues to aid communication, organizational skills, and self-management. The Picture Exchange Communication System provides a visual system in which to learn communication. Social Stories intervention increases appropriate behavior by explaining social situations in ways understandable to the student. Medications, especially atypical antipsychotics, can ameliorate specific symptoms such as aggressive or self-injurious behavior. Children treated early can usually be taught, to varying degrees, to communicate, recognize and respond to social interactions, develop imaginative play, and curb all-consuming repetitive self-stimulatory behaviors.

Prevention of secondary complications: Intensive behavioral intervention programs can prevent or at least mitigate aggressive behaviors (tantrums, aggression, and self injurious behaviors) that occur commonly in children with no communication skills or interest in social interactions.

Testing of relatives at risk: Because sibs are at increased risk of developing autism or an ASD, their language, development, and behavior should be closely monitored for the first three years, preferably through an autism sib program.

Genetic counseling. For individuals with autism in whom the etiology is known, genetic counseling and risk assessment are based on the genetics of that specific diagnosis. For autism of unknown cause, the empiric aggregate risk to sibs is 5%-10% for autism and 10%-15% for milder conditions, including language, social, and psychiatric disorders. For families with two or more affected children, the recurrence risk approaches 35%. Male sibs (brothers) of a proband with essential autism have a 7% risk for autism and an additional 7% risk for milder ASD. Female sibs (sisters) of a proband with essential autism have a 1% risk for autism; the risk for a milder ASD is unknown. The recurrence risk to sibs of a proband with complex autism is 1% for autism and an additional 2% for a milder ASD.

Definition

Clinical Manifestations

Autism spectrum disorders (ASD) develop prior to age three years. Infants typically do not care to be held or cuddled and do not reach out to be picked up. Often they are "colicky" and hard to console, typically quieting more readily when left alone. They may avoid and fail to initiate eye contact or stare into space. Sleep disturbances and sensory issues may be noted in the first year. Despite early signs, children with ASD often do not come to medical attention until after the second year when language delays are obvious.

For most children, the onset of ASD symptoms is gradual; however, approximately 30% have a "regressive" onset. These children begin to speak and then, either gradually or precipitously, lose language and become distant. Within a matter of days, the child may refuse to make eye contact and stop responding to his/her name. Deafness is often suspected, although hearing tests are normal. Repetitive movements may develop immediately or not until the child is age three or four years. Though it has been debated whether these children are well and then become damaged by some exogenous exposure, the best evidence, including retrospective analysis of first birthday videotapes and neuropathologic studies, suggests their regressive course is genetically determined [Lord et al 2004, Volkmar et al 2005, Werner & Dawson 2005, Stefanatos 2008].

Approximately 25% of children who fit the diagnostic criteria for ASD at age two or three years subsequently begin to talk and communicate and by age six or seven years blend to varying degrees into the regular school population. Even for this group, social impairments generally continue. For the remaining 75%, most have some improvement with age but continue to require parent, school, and societal support. Excellent reviews of outcomes are provided by Howlin et al [2000], Howlin et al [2004], Seltzer et al [2004], and Farley et al [2009]. Some studies indicate that fewer than 5% of children with autism completely recover [Nordin & Gillberg 1998]; however, loosening of diagnostic criteria to include less impaired children appears to be increasing that number. A 20-year follow-up of adults between ages 22 and 46 years diagnosed with autism and average or near-average cognitive abilities in the 1980s found that half the individuals functioned quite well and half were employed in full-time or part-time paying jobs; however, only 12% lived independently and 56% lived with their parents [Farley et al 2009].

Autism spectrum disorders are defined completely on the basis of three areas of behavioral impairment:

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Impairments in social interaction. Impairment in social interaction distinguishes individuals with autism from those around them. Children with classic autism are unable to "read" other people, ignoring them and often strenuously avoiding eye contact. Typically, they do not comfort others or seek comfort and do not share interests with others, such as bringing toys or pictures to their parents. Rather, they use their parents as objects, and may climb on them to get to a desired object, pull the parent by the hand, or place the parent's hand on the object, as if the child were using a tool. In clinic, the child who is content to turn pages of a magazine or spin the wheels of a car may become agitated when a simple examination is attempted. At home, the child with autism usually prefers to be by himself, engaging in his own, often repetitive, activities. The lack of functional or spontaneous make-believe play is characteristic. Toys are lined up, sorted, twirled, or hurled, but are not used for imaginative games or imitation of day-to-day activities, such as feeding the baby or washing the dishes. When play emerges later, it is stylized and not spontaneous. Children with autism fail to develop friendships with peers and siblings. In school, they often stand and watch other children from a distance. Some children respond to social overtures but take little social initiative, while others seek interaction but have little sense of how to proceed toward normal friendships.
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Impairments in communication. Children with autism fail to develop reciprocal communication either by speech, gestures, or facial expressions. Characteristically, young children fail to use eye gaze or pointing to communicate and direct their parent’s attention. Early pragmatic skills are limited and are characterized by typical rates of requesting but substantially reduced rates of social interaction and establishing joint attention. Deficits in pragmatic skills are present throughout life and affect both language and social interaction. The young child appears unable to grasp the concept that speech can be used to name objects, to request a toy, or to engage others. In contrast to the child with nonspecific intellectual disability or a primary developmental language disorder who usually has better receptive than expressive language, the child with autism has impaired receptive language. When children with autism learn to talk, they display stereotypic speech that may involve echolalia, pronoun reversal, and unusual inflections and intonations. Unlike typically developing children who begin talking using one-word utterances, children with autism may begin talking in "chunks" composed of commercials, movies, or others' speech. These chunks often convey idiosyncratic meanings and the child with autism has no understanding of the conventional meaning of the individual words. Pragmatic difficulties including difficulties sustaining a conversation, turn taking, and allowing the conversational partners to introduce their topics, usually continue despite improvement in expressive speech. [Lord et al 2004].
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Repetitive and stereotypic behaviors. Infants may stare or rock. Toddlers may have motor "stereotypies" such as movements of fingers, twirling strings, flicking pages of books, or licking. Repetitive whole body movements may include spinning and running back and forth. The repetitive behaviors often have a visual component such as holding the fingers to the side of the face and watching them with a sideways glance. Sometimes the movements become more complex with an individualized sequence of patting, rubbing, or twirling. These stereotypies may last for hours. Though the cause of the repetitive movements is unclear, they seem to have a calming effect and may (especially in the older child) surface in times of stress. This repetitiveness is reflected in a rigid need for sameness in daily routines. Children with autism can develop elaborate rituals in which the order of events, the exact words, and the arrangement of objects must be followed. Failure of parents/caretakers to follow the proscribed order of events results in inconsolable outbursts.

Other symptoms occurring in a substantial number of individuals with autism spectrum disorders:

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Hyper- and hyposensitivities to sound and touch. Loud or high-pitched noises such as the vacuum cleaner cause great discomfort, causing the child to hold his hands over his ears. The feel of certain clothes or of being touched may be unbearable; conversely, truly painful stimuli like a burn or laceration are ignored.
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Odd behaviors around foods and their presentation, such as accepting a limited number of foods or only eating french fries that come from McDonalds®.
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Abnormal sleep patterns (60%), such as never sleeping through the night, trouble going to sleep, or getting up for the day at 2:00 am.
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Tantrums and/or self-injurious and aggressive behaviors brought on by a change in routine, an offending touch, being asked to do something they do not want to do, or for no apparent reason.
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Impaired motor development with toe walking early in life, hypotonia, general clumsiness, and inability to ride a two-wheel bicycle.
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Total disregard for danger, resulting in high risk of early death, commonly from drowning.

Evidence suggests that as many as 15% of adolescents or young adults with autism develop a catatonia syndrome associated with marked deterioration in movement with slowness and freezing in mid-movement, vocalizations, and regression of self-care skills.

Obesity is a common complication of unknow cause. Medication side-effects, inactive life style and difficulty withholding food from children with aggression may be implicated.

Delineation of ASD subgroups. In an attempt to sort out the clinical and etiologic heterogeneity within autism, researchers are increasingly emphasizing the identification of phenotypic features (endophenotypes or biomarkers) to delineate subgroups that could predict outcomes and direct treatment choices [Viding & Blakemore 2007]. The terms “endophenotypes” and “biomarkers” imply that these neurophysiologic, biochemical, endocrinologic, neuroanatomic, and cognitive features are more biologic and, thus, more proximally related to the underlying etiologic processes than the behavioral symptoms [Gottesman & Gould 2003].

The following phenotypes have been investigated:

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IQ scores in longitudinal studies strongly predict long-term outcomes and are directly associated with the degree of autistic psychopathology even in young children [Lord et al 2001, Howlin et al 2004, Chawarska & Bearss 2008]. Stevens et al [2000] reported that early normal or near-normal nonverbal IQ is the best predictor of adequate functioning by grade school; however, in the presence of significant language addition, uneven cognitive profiles typical of autism may make an average of widely discrepant scores meaningless [Klin et al 2005a]. That said, 50% to 70% of autistic children have historically been classified as intellectually disabled by nonverbal IQ testing [Fombonne 2005, Baird et al 2006]. An epidemiologic study from the Centers for Disease Control and Prevention reported 44.6% of the ASD population had intellectual disability. Lower rates of intellectual disability reported in more recent studies are probably the result of broadening of the ASD diagnostic criteria to include Asperger syndrome and children with milder symptoms [Autism and Developmental Disabilities Monitoring Network 2009].
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Seizures develop in approximately 25% of children with autism. In addition, the rate of electroencephalographic abnormalities is increased in children with autism who do not have a history of seizures [Kim et al 2006, Spence & Schneider 2009]. As in the general population, seizures alone are not a sensitive predictor of outcome. However, the prevalence of seizures is higher among individuals with moderate to severe intellectual disability and those with motor deficits [Tuchman & Rapin 2002]. And individuals with autism plus epilepsy have on the average lower IQs and poorer adaptive, behavioral, and social outcomes than those without epilepsy [Hara 2007].
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Structural brain malformations, typically identified by MRI, usually portend a poorer outcome [Miles & Hillman 2000]. In a recent study of 77 children with autistic disorder of unknown cause and uncomplicated by seizures, severe intellectual disability, major anomalies, or focal neurologic signs, neuroradiologists reported that 40% had some abnormality, of which white-matter signal abnormalities, severely dilated Virchow-Robin spaces, and temporal lobe structural abnormalities were the most common [Boddaert et al 2009]. This level of pathology in children with nonsyndromic autism lends support to the controversial recommendation to obtain brain MRIs as a standard diagnostic test in autism.
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Significant generalized dysmorphology, found in 15% to 20% of individuals with autism, is a reliable indicator of an insult to early development [Miles & Hillman 2000]. Using a classification system that defines generalized dysmorphology, Miles et al [2005] found that in 81% of individuals dysmorphology was predictive of a poor outcome (defined as nonverbal with IQ <55). The presence of significant dysmorphology was also the top predictor of a poor response to early intensive behavioral therapy [Stoelb et al 2004]. The Autism Dysmorphology Measure (ADM), which guides clinicians through an assessment of 12 body areas, was developed to provide non-geneticists with a standardized method for assessing generalized dysmorphology [Miles et al 2008]. The 12 areas assessed are: height, hair growth pattern, ear structure, size and placement, nose size, face size and structure, philtrum, mouth and lips, teeth, hand size, fingers and thumbs, nails, and feet.
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Microcephaly (head circumference <2nd centile) occurs in 5%-15% of children with autism [Fombonne et al 1999, Miles et al 2000, Miles et al 2005] and is highly predictive of poor outcome.
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Macrocephaly (head circumference greater than the 97th centile), found in approximately 30% of children with autism, does not strongly correlate with outcome or IQ [Miles et al 2000] though Lainhart noted an association with delay in acquisition of first words [Lainhart et al 2006].
Using dysmorphology and microcephaly, autism can be defined as complex or essential [Miles et al 2005]:
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Complex autism is defined by the presence of dysmorphic features and/or microcephaly, features which indicate some alteration of early morphogenesis. Approximately 20%-30% of children ascertained because of a diagnosis of autism have complex autism. Complex autism is associated with a poorer prognosis, a lower male-to-female ratio, and a lower sibling recurrence risk than essential autism. Approximately 30% of children with complex autism can be diagnosed with an autism associated syndrome or chromosome disorder using currently available diagnostic tests (see Causes of Autism) [Miles et al 2008].
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Essential autism is defined by the absence of generalized dysmorphology and microcephaly. Approximately 70%-80% of children with autism have essential autism. Children with essential autism are more likely to be male, to have a higher sibling recurrence risk, and to have a greater family history of autism and autism-related disorders such as alcoholism and depression than children with complex autism. As a group, the outcome is better for essential autism than complex autism, though most children with essential autism still do poorly. Currently available testing is less likely to reveal an exact etiologic diagnosis in essential autism than in complex autism.
Establishing the Diagnosis
The American Psychiatric Association Manual of Psychiatric Diseases, 4th edition, is the primary diagnostic reference for autism used in the US. The update in 2000 changed some of the accompanying text but did not change the diagnostic criteria. (See American Psychiatric Association [2000].)
The DSM-IV in 1994 placed autistic disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified (PDD-NOS) under the umbrella diagnostic term ‘pervasive developmental disorders.’ Subsequently, discovery of MECP2 mutations as the cause of Rett syndrome, uncertainty about nosology of childhood disintegrative disorder, and better understanding of the continuity within the autism diagnoses led to adoption of the term autism spectrum disorders (ASD) as the favored umbrella designation for autistic disorder (AD), Asperger syndrome (AS) and PDD-NOS (National Institute of Mental Health). It is expected that the DSM-V, due out in 2012, will further simplify the nosology.
Autistic Disorder— DSM-IV Diagnostic Criteria (diagnostic code 299.00)
I.
A total of six (or more) items from A, B, and C, with at least two from A, and one each from B and C:
A.
Qualitative impairment in social interaction, as manifested by at least two of the following:
B.
Qualitative impairments in communication as manifested by at least one of the following:
1.
Marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures to regulate social interaction
2.
Failure to develop peer relationships appropriate to developmental level
3.
A lack of spontaneous seeking to share enjoyment, interests, or achievements with other people (e.g., by a lack of showing, bringing, or pointing out objects of interest)
4.
Lack of social or emotional reciprocity
5.
Delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime)
6.
In individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others
7.
Stereotyped and repetitive use of language or idiosyncratic language
8.
Lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level
9.
Encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus
10.
Apparently inflexible adherence to specific, nonfunctional routines or rituals
11.
Stereotyped and repetitive motor mannerisms (e.g., hand or finger flapping or twisting or complex whole-body movements)
12.
Persistent preoccupation with parts of objects
C.
Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:
II.
Delays or abnormal functioning in at least one of the following areas, with onset prior to age three years: 1) social interaction, 2) language as used in social communication, or 3) symbolic or imaginative play
III.
The disturbance is not better accounted for by Rett syndrome or childhood disintegrative disorder.
Asperger syndrome [Asperger 1944, Frith 1991 (English translation)] is characterized by relatively normal language development (including timing, grammar, and vocabulary) but requires all other DSM-IV diagnostic criteria for autism. Individuals with Asperger syndrome are generally loners, are uncomfortable in groups, are unable to empathize with others, do not chat, follow a literal interpretation of speech with no understanding of idioms or jokes, maintain a sameness in routine, follow strict rules, and have an encompassing preoccupation with one domain, such as the weather or computers. Speech may be pedantic or repetitive with odd intonations. IQ must be within the normal range to qualify for the diagnosis. Clumsiness is common. Whether Asperger syndrome is the expression of the high end of the autism spectrum or a discrete genetic entity is unclear.
The diagnosis of Asperger syndrome is problematic, with poor concordance between the various diagnostic instruments [Klin et al 2005b]. The Autism Spectrum Screening Questionnaire (ASSQ) [Ehlers et al 1999], the Asperger Syndrome Diagnostic Interview (ASDI) [Gillberg et al 2001], the Australian Scale for Asperger's Syndrome [Garnett & Atwood 1997], and the Childhood Asperger Syndrome Test (CAST) [Scott et al 2002] are also available. A recent video, Asperger's Diagnostic Assessment [Attwood 2004] provides a hands-on tutorial which should be useful to the clinician.
Pervasive developmental disorder - not otherwise specified (PDD-NOS). Children with autistic symptoms who do not meet full criteria in all three diagnostic domains can be diagnosed with PDD-NOS. This includes children with milder symptoms of all three autism diagnostic criteria and those meeting full criteria for autism in two of the three domains. Sometimes PDD-NOS is used as an initial or tentative diagnosis for younger children or before diagnostic evaluations are completed.
Broader autism phenotype (BAP) may designate siblings or other family members with some autism symptoms [Piven & Palmer 1999, Pickles et al 2000, Geschwind et al 2001]. This terminology was originally adopted by researchers to classify sibs who were likely to have mutations in putative autism genes and reflects the growing awareness of the broad phenotypic spectrum of autism spectrum disorders.
Childhood disintegrative disorder is a rare condition manifesting before age ten years in which children who have developed normally for at least two years deteriorate and lose previously acquired language, social, and play skills. The condition may resemble autism in clinical presentation but differs from autism in the pattern of onset, course, and outcome. It is no longer considered one of the pervasive developmental disorders.
Diagnostic and Screening Tools
To diagnose autism, one must precisely enumerate the autism symptoms and their age of occurrence, which can be done using the DSM-IV or a number of checklists [Filipek et al 2000, Cavagnaro 2007]:
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CARS (Childhood Autism Rating Scale) [Schopler et al 1986] consisting of 15 questions scored by the parent and the tester is the most commonly used diagnostic checklist. It is a reliable, well-verified measure which is relatively fast and easy to administer. A score of 30 to 35 indicates mild autism and 36 or higher moderate-to-severe autism.
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ABC (Autism Behavior Checklist) [Aman et al 1985]
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GARS (Gilliam Autism Rating Scale) [Gilliam 1995]
In North America, research criteria for the diagnosis of autism depend primarily on the ADI-R (Autism Diagnostic Interview-Revised) [Lord et al 1994], which is a detailed parent interview, and the somewhat shorter ADOS (Autism Diagnostic Observation Schedule) [Lord et al 1989]. Both scales follow the DSM-IV criteria and were developed in an attempt to sort autism by its behavioral symptoms to permit identification of homogeneous populations. These scales are not widely used in clinical practice because of the time and expense to administer, although the shorter ADOS is becoming more widely used outside of research settings.
To guide allocation of services school systems use educationally based “autism eligibility” criteria which are similar but not identical to the medical diagnostic criteria, sometimes leading to conflicts. This is particularly true for the higher-functioning or Asperger syndrome students whose behavioral manifestations need remediation through the schools, but may not meet the educational egibility criteria.
It is recommended that all children be screened for autism by their primary health care provider. A positive score on one of these tools is not diagnostic for an ASD but prompts referral to a diagnostic clinic.
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M-CHAT (Checklist for Autism in Toddlers-modified) [Robins et al 2001] is the most commonly used screening tool. This 23 item checklist, designed for primary care providers to identify at-risk toddlers at the 18-month visit, can be filled out by parents in the waiting room and is available in Spanish and English [Cavagnaro 2007]. A recent replication study [Kleinman et al 2008] confirmed the validity in detecting possible ASD in both low- and high-risk groups aged 16 to 30 months. It is recommended by the Neurology Quality Standards Subcommittee [Filipek et al 1999, Filipek et al 2000].
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Infant/Toddler Checklist (pdf) from the Communication and Symbolic Behavior Scales Developmental Profile [Wetherby & Prizant 2002] is recommended by the American Academy of Pediatrics to identify at-risk children younger than age 18 months [Johnson & Myers 2007].
Prevalence
An increase in the prevalence of all the autism spectrum disorders is being reported worldwide.
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Prior to 1990, most studies estimated a general population prevalence for autism of four to five per 10,000 (1/2000-1/2500) [Fombonne 2001].
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During the 1990s, studies of preschool children in Japan, England, and Sweden reported prevalence rates for autism of 21 to 31 per 10,000 (1/476 -1/323) [Arvidsson et al 1997, Baird et al 2000].
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A CDC case-finding study in Brick Township, New Jersey reported prevalence at 40 per 10,000 (1/250) for autism and 67 per 10,000 (1/149) for all PDDs [Autism and Developmental Disabilities Monitoring Network 2009].
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An epidemiologic study from the United Kingdom utilizing specialized visiting nurses who monitor child health and development at ages seven months, 18 to 24 months, and three years reported a prevalence rate of 16.8 per 10,000 (1/595) for autism and 63 per 10,000 (1/159) for all PDDs in children younger than age five years [Chakrabarti & Fombonne 2001]. Those rates were confirmed, reporting a prevalence rate of 22 per 10,000 (1/455) for autism and 59 per 10,000 (1/169) for all PDDs in children younger than age six years [Chakrabarti & Fombonne 2005].
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Two recent studies in the United States reported the diagnosis of an ASD in 1/91 children age three to seventeen years [Kogan et al 2009] and 1/110 children age eight years [Autism and Developmental Disabilities Monitoring Network 2009].
Recent analyses indicate that the “autism epidemic” does not reflect a true increase in the incidence of ASD, but is attributable to increased awareness by both the public and professionals, leading to more complete case finding together with broadening of the diagnostic criteria [Gernsbacher et al 2005, Fombonne et al 2006, Shattuck 2006, Taylor 2006, Atladottir et al 2007].
Studies finding the greatest increase in ASD also note lower rates of intellectual disability in these children. Only 30% of children with PDDs ascertained by Chakrabarti & Fombonne [2005] were intellectually disabled compared with 70% of children in earlier studies. This suggests that many of the higher-functioning children with milder autistic symptoms, such as less severe language impairment and fewer aggressive behaviors had not been counted in past epidemiologic surveys.
A recent update on the ongoing epidemiologic surveillance of autism in California indicated that the rise of autism in California shows no sign of plateauing. The study concluded that earlier age at diagnosis and inclusion of milder cases accounted for more than two-thirds of the increase but stated that the extent to which the continued rise could represent a true increase in the occurrence of autism remains unclear [Hertz-Picciotto & Delwiche 2009].
Causes of Autism

Twin and family studies have established the preponderant genetic basis of autism and indicate that the heritability of autism is over 90% [Monaco & Bailey 2001]. Currently a genetic cause can be identified in 20% to 25% of children with autism. A small number of cases of autism can be traced to specific teratogenic exposures. The cause of autism in the remaining 75% to 80% remains unknown.

The growing number of distinct, individually rare genetic causes of autism suggests that the genetic basis of autism resembles that of intellectual disability and cerebral palsy with many syndromes, each individually rare, implicated in the development of autism. But it also seems likely that complex and as-yet-undetermined interactions between “small-effect” inherited changes will also be found to be causative.
Genetic Causes

Single gene disorders in which neurologic findings are associated with ASD (~5%)

Cytogenetically Visible Chromosomal Abnormalities

High-resolution chromosome analysis reveals chromosome aneuploidy in approximately 5% of children with ASD. Another 3%-5% have identifiable chromosomal abnormalities using FISH techniques. As expected, unbalanced chromosome abnormalities are found predominantly in children with autism and accompanying dysmorphology [Miles et al 2005, Jacquemont et al 2006, Takahashi & Miles 2009].

Although cytogenetic abnormalities on almost every chromosome have been found in autism, only a few occur commonly enough to be possible loci for autism genes [Wassink et al 2001, Reddy 2005, Vorstman et al 2006]. A curated database of chromosome abnormalities reported in individuals with autism is available at projects.tcag.ca/autism [Marshall et al 2008].

Maternally derived duplication of the Prader-Willi/Angelman syndrome critical region (15q11-q13) is the most commonly observed chromosome abnormality in autism, detected in 1%-3% of children with autism. Most commonly this duplication is the result of a de novo supernumerary isodicentric 15q chromosome and less commonly the result of segregation of a parental chromosome translocation or a maternally derived interstitial 15q duplication. Routine cytogenetic analysis detects supernumerary isodicentric 15q but the diagnosis of interstitial duplications requires interphase FISH analysis or aCGH. The maternally derived 15q11-q13 interstitial duplication is a highly penetrant cause of autism, whereas the paternally derived duplication has little or no phenotypic effect, indicating the significance of genomic imprinting of this region [Hogart et al 2010].

A maternal duplication of 15q, resulting in trisomy for that region, causes subtle effects on the physical phenotype whereas,children with four copies of 15q including those with a supernumerary isodicentric 15 are typically more impaired and may exhibit hypotonia, seizures, microcephaly, and severe developmental delay [Borgatti et al 2001, Dykens et al 2004, Hogart et al 2010].

Trisomy 21. Children with Down syndrome have autism more commonly than expected. The incidence was at least 7% in one study [Kent et al 1999].

45, X Turner syndrome. Girls and women with Turner syndrome who have a maternal X chromosome (45,Xmat) have poorer social cognition skills than girls who have a paternal X chromosome (45,Xpat) [Skuse 2000].

Array comparative genomic hybridization (aCGH) is steadily replacing high-resolution chromosome analysis and FISH in the evaluation of children with autism. Clinically available platforms used in aCGH are designed to test for known deletion/duplication syndromes on the entire genome plus assessment of subtelomeric regions. The platforms used in aCGH vary in the density and type of molecular markers (BAC, SNP, and oligonucleotide clones) and are constantly being upgraded as new CNV hot spots are identified.

Using a 1-Mb genome-wide array, Jacquemont et al [2006] identified clinically relevant CNVs in 27.5% (8/29) of individuals with autism and dysmorphology, who previously had a normal karyotype as determined by routine cytogenetic studies.
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Using an oligonucleotide array, Sebat et al [2007] found de novo copy number changes in 10% of children from simplex families (i.e., autism in a single family member) and 2% from multiplex families (i.e., autism in multiple family members) compared to 1% in controls.
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Using a dense genome-wide SNP array, Marshall et al [2008] found unbalanced CNVs in 44% of 427 unrelated families with autism that were not present in control families. Many of these CNVs were inherited and only 7% were de novo in persons with autism of unknown cause.
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A whole-genome CNV study using 550,000 SNP markers on a cohort of 859 individuals with ASD and 1,409 healthy children of European ancestry revealed several pathogenic genomic changes in genes encoding neuronal cell-adhesion molecules (NRXN1, CNTN4, NLGN1, and ASTN2) and in genes involved in the ubiquitin pathways (UBE3A, PARK2, RFWD2, and FBXO40) [Glessner et al 2009].

These studies highlight the potential of array-based techniques. At this time, however, caution must be exercised in interpreting these results and their relation to autism. The de novo occurrence of a copy number variation is not absolute evidence of its pathogenicity. Distinguishing characteristics of pathogenic CNVs include (1) de novo event not found in either parent or inherited from an affected parent, (2) deletions or duplications which include genes known to be expressed in the brain, (3) large CNVs, and (4) deletions, as opposed to duplications

Some CNVs associated with autism include the following:

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16p11.2 deletion syndrome is characterized by developmental delay, intellectual disability, and/or autism spectrum disorder (ASD). Developmental delays are more related to diminished language and cognitive function than motor disability. Although IQ scores range from mild intellectual disability to normal, those with IQ scores in the average range typically have other developmental issues such as language delay or ASD. Expressive language appears to be more affected than receptive language. Weiss et al [2008] reported 16p11.2 deletions or duplications in approximately 1% of individuals with autism and 1.5% of children with developmental or language delays. Marshall et al [2008] observed a similar 1% frequency.

The 16p11.2 deletion often occurs de novo, but may be transmitted from parent to child in an autosomal dominant manner. Of note, however: the same 16p11.2 CNVs can be observed in a variety of other disorders including schizophrenia, bipolar disorder, seizures, ADHD, and dyslexia, as well as apparently unaffected family members; thus, interpretation of the significance of this CNV can be difficult [McCarthy et al 2009, Rosenfeld et al 2010, Shinawi et al 2010].

This CNV is located at a hot spot of genomic instability caused by duplicated blocks of DNA that lead to unequal crossing over during meiosis and is detectable by clinical oligonucleotide aCGH platforms and some bacterial artificial chromosome (BAC)-based platforms. Other test methods that can detect this deletion include multiplex ligation-dependent probe amplification (MLPA), metaphase fluorescence in situ hybridization (FISH), and quantitative polymerase chain reaction PCR (qPCR).
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The following singe gene disorders are commonly observed to cause syndromic autism.

Fragile X syndrome. Whereas 1% to 3% of children ascertained on the basis of an autism diagnosis have fragile X syndrome, at least half the children with fragile X syndrome have some autistic behaviors, including avoidance of eye contact, language delays, repetitive behaviors, sleep disturbances, tantrums, self-injurious behaviors, hyperactivity, impulsiveness, inattention, and sound sensitivities. In one study of 63 males with fragile X syndrome, 30% met criteria for autistic disorder and 30% criteria for PDD-NOS [Harris et al 2008].

Fragile X syndrome is caused by expansion of the CGG trinucleotide repeat in the FMR1 gene to the full mutation size of 200 or more CGG repeats.

A considerable number of children being evaluated for autism are found to have FMR1 premutations (55-200 CGG repeats) [Goodlin-Jones et al 2004, Cornish et al 2005, Reddy 2005, Farzin et al 2006, Loesch et al 2007]. Farzin et al [2006] studied 14 boys with premutations ascertained through an autism clinic and found 71% met ASD diagnostic criteria. In the authors’ experience, ten of 488 (2%) persons ascertained through a dedicated autism clinic had either an FMR1 full mutation or premutation. Of the five children with a full mutation, only one was diagnosed with autistic disorder; four did not meet criteria for an ASD diagnosis. For the five premutation carriers, four were diagnosed with autistic disorder and one with PDD-NOS [Takahashi & Miles 2009]. This underscores the importance of performing FMR1 molecular genetic testing in all children being evaluated for an autism spectrum disorder.

PTEN macrocephaly syndrome. The PTEN (phosphatase and tensin homolog) gene was initially described as a tumor suppressor gene associated with a broad group of disorders referred to as PTEN hamartoma tumor syndrome which includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Lhermitte-Duclos disease. More recently, PTEN gene mutations have been associated with autism and macrocephaly [Zori et al 1998, Parisi et al 2001, Delatycki et al 2003, Butler et al 2005, Buxbaum et al 2007a]. Correspondingly, PTEN is recognized to play an important role in brain development, including neuronal survival and synaptic plasticity.

The frequency of PTEN mutations as a cause of ASD is unclear; results from studies of children ascertained through autism and macrocephaly range from 1% [Buxbaum et al 2007a] to 8.3% [Varga et al 2009] to 17% [Butler et al 2005]. Both de novo and familial PTEN mutations have been identified in this population. It may be significant that more of the children studied by Buxbaum et al [2007a] were from multiplex families, whereas the children studied by Butler et al [2005] were from simplex families.

Children with ASD found to have a PTEN mutation generally have extreme macrocephaly ranging from +3.7 SD to +9.6 SD (average: +5.4 SD) [Buxbaum et al 2007a]. In addition, mutation of PTEN is not specific for autism: Varga et al [2009] found children with macrocephaly and intellectual disability but not autism had a similar chance of having a PTEN mutation.

Because PTEN germline mutations are associated with the phenotypically broad PTEN hamartoma tumor syndrome, it is recommended that children with PTEN mutations and their families be evaluated by a medical geneticist for clinical signs of any of the related disorders. Moreover, because these disorders carry a risk of cancer, including cancer of the breast, thyroid, endometrium, and kidney, these individuals need to be involved in a tumor surveillance program. See PTEN Hamartoma Tumor Syndrome.

Sotos syndrome. Sotos syndrome is characterized by the cardinal features of typical facial appearance, overgrowth (height and head circumference ≥2 SD above the mean), and learning disability ranging from mild (children attend mainstream schools and are likely to be independent as adults) to severe (lifelong care and support are required). Sotos syndrome is associated with the major features of behavioral problems, congenital cardiac anomalies, neonatal jaundice, renal anomalies, scoliosis, and seizures. Though Sotos syndrome is probably not a significant cause of classic autism [Buxbaum et al 2007b], children with Sotos syndrome and behavioral problems such as difficulty with peer group relationships and lack of awareness of social cues may be referred to autism clinics.

Eighty to 90% of individuals with Sotos have a demonstrable mutation or deletion of NSD1; inheritance is autosomal dominant.

Rett syndrome is one of the original DSM-IV-designated pervasive developmental disorders and the only one for which a specific genetic etiology has been identified [Amir et al 1999]. Ninety-six percent of individuals with classic Rett syndrome have mutations in the X-linked MECP2 gene [Moretti & Zoghbi 2006]. Though the vast majority of individuals with MECP2 mutations are girls, MECP2 mutations are identified in 1%-2% of males with developmental disorders, including infantile encephalopathy, intellectual disability with motor deficits and early-onset bipolar disorder and schizophrenia. Most males are identified in families with an X-linked pattern of intellectual disability.

The phenotype of MECP2-confirmed Rett syndrome overlaps considerably with autism of unknown cause; children with both often have a period of normal development followed by loss of language with stereotypic hand movements. However, Rett syndrome can usually be distinguished clinically based on a decreasing rate of head growth, progressive gait disturbance, and hand-wringing in early childhood. Initially, the distinction may be difficult: a study of two Rett syndrome databases found that 17.6% (55/313) of girls with MECP2-confirmed Rett syndrome had been given an early diagnosis of autism [Young et al 2008]. Those girls had significantly milder Rett syndrome symptoms, were more likely to remain ambulatory, retained some functional hand use, and developed specific Rett syndrome symptoms later. They were also more likely to have the mutation p.Arg306Cys or p.Thr158Met. The recommendation of Young et al [2008] that all girls diagnosed with autism be monitored carefully for evolving signs of Rett syndrome (including a deceleration in head growth) seems justified.

Overall, MECP2 mutations have been reported in approximately 1% of children diagnosed with autism [Moretti & Zoghbi 2006, Lintas & Persico 2009]. It is not clear at this time whether this justifies MECP2 molecular genetic testing in girls diagnosed with apparently classic autism, especially girls who will be followed on a regular basis in a clinic with expertise in both disorders.

Evidence of variable expression of the protein MeCP2 in the brains of individuals with both autism and Rett syndrome and evidence that MeCP2 deficiency can reduce expression of the genes UBE3A and GABRB3 implicated in autism, indicate some causal relationship between the two disorders [Samaco et al 2004, Samaco et al 2005]. Intensive study of the role of MeCP2 in maintaining neuronal function and evidence of symptom reversal of neuronal symptoms in mice following reactivation of the silenced Mecp2 gene is projected to have implications for autism treatment [Bird 2008].

In a prospective study of children with TSC evaluated using the ADOS, 66% of infants met criteria for autism or ASD at age 18 months, 54% at age 24 months, 46% at age 36 months, and 50% at age 60 months.The children with both TSC and autism were more cognitively impaired than those with TSC only [Jeste et al 2008].

An evaluation for signs of TSC including skin lesions (hypopigmented macules, shagreen patches, adenoma sebaceum) and a family history consistent with autosomal dominant inheritance of findings suggestive of TSC (seizures, skin lesions, intellectual disability) are generally sufficient to indicate or rule out the diagnosis of TSC in children with autism. Molecular genetic testing for the two causative genes, TSC1 and TSC2, is clinically available. Recurrence risks for families with a child with autism associated with TSC may be significantly higher than for for families with autism of unknown cause. Mechanisms underlying autism in TSC are unknown.

Neurofibromatosis type 1 (NF1). Although NF1 has been diagnosed in children with autism, it is unclear whether this is a true association or the chance simultaneous occurrence of two relatively common childhood disorders [Fombonne et al 1997b, Battaglia & Carey 2006, Schaefer & Lutz 2006]. No genetic overlap between mutations in the NF1 gene and autism has been demonstrated [Zafeiriou et al 2007].

Joubert syndrome. This autosomal recessive disorder is characterized by partial or complete agenesis of the cerebellar vermis, seen as the “molar tooth sign” on MRI, abnormal breathing, abnormal eye movement, cognitive impairment, and behavioral problems. A subset of Joubert syndrome appears related to the AHI1 gene, encoding the ‘jouberin’ protein [Alvarez Retuerto et al 2008]. In one study, three of 11 children with Joubert syndrome met diagnostic criteria for autism and one of 11 for PDD-NOS [Ozonoff et al 1999]. However, Takahashi et al [2005] delineated behavioral and genetic differences between autism and Joubert syndrome, implying that they are etiologically distinct disorders. In a report by Muhle et al [2004] of monozygotic twins with Joubert syndrome, the twin with the more severe cerebellar abnormality had autism, suggesting that some disorders may have the potential to cause the autism phenotype if as-yet unidentified autism regions or circuits of the brain are affected.

Metabolic conditions

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Mitochondrial disorders. Although mitochondrial respiratory chain disorders have only been reported in individuals with autism on rare occasions, elevated plasma concentrations of lactate have been frequently noted [Coleman 2005, Correia et al 2006]. A population-based study of 69 children with autism reported an elevated plasma lactate concentration in 20% (14/69); five of the eleven children undergoing muscle biopsy had a deficiency of one or more respiratory chain complexes, most frequently complexes I, IV, and V, based on enzymatic complex activity less than 20% of normal [Oliveira et al 2005]. If confirmed, this would be the largest etiologic autism subgroup. Identifying a mitochondrial disorder is more likely in autistic children with atypical features such as hypotonia, failure to thrive, and intermittent episodes of regression than in children without these findings. Weissman et al [2008] analyzed data from 25 persons with a mitochondrial disorder and an initial diagnosis of autism and found they could all be distinguished from autism of unknown cause on the basis of an abnormal neurologic examination and/or an elevated plasma lactate concentration. In addition, mitochondrial dysfunction has also been reported in persons with ASD without additional neurologic features [Pons et al 2004, Smith et al 2009].
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Phenylketonuria (PKU). Co-morbidity of ASD and untreated PKU has been described but the autism diagnosis is usually complicated by the severe intellectual disability found in these children. A systematic study showed that none of 62 persons with PKU who were diagnosed and treated early met diagnostic criteria for autism, whereas two of 35 (5.7%) persons with PKU who were diagnosed late fulfilled the diagnostic criteria for ASD [Baieli et al 2003].
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Adenylosuccinate lyase deficiency. This rare autosomal disorder of de novo purine synthesis results in the accumulation of succinylpurines in body fluids. In about half of affected individuals the variable clinical manifestations include developmental delay, seizures, and autism symptoms including failure to make eye contact, repetitive behavior, agitation, temper tantrums, and aggression [Van den Berghe et al 1997]. In one study, one out of 420 children with PDD was found to have adenylosuccinate lyase deficiency [Stathis et al 2000].
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Creatine deficiency syndromes (CCDSs). The CCDSs, inborn errors of creatine metabolism, include the two creatine biosynthetic disorders, guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency (or GATM deficiency), and the creatine transporter defect, SLC6A8 deficiency. Intellectual disability and seizures are common to all three CCDSs. Approximately 80% of individuals with GAMT deficiency have a behavior disorder that can include autistic behaviors and self-mutilation; approximately 45% have pyramidal/ extrapyramidal findings. Onset is between ages three months and three years. Only five individuals with AGAT deficiency have been reported. The phenotype of SLC6A8 deficiency in affected males ranges from mild intellectual disability and speech delay to severe intellectual disability, seizures, and behavioral disorder. Onset is between ages two and 66 years. Approximately 50% of females heterozygous for SLC6A8 deficiency have learning and behavior problems.

The prevalence of creatine deficiency syndromes in those with ASD appears to be low. Sequencing of the SLC6A8 gene in 100 males with ASD did not detect deleterious mutations [Newmeyer et al 2007].
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Smith-Lemli-Opitz syndrome (SLOS). This autosomal recessive multiple congenital anomaly and intellectual disability syndrome is caused by a deficiency of 7-dehydrocholesterol reductase, an essential enzyme in the biosynthesis of cholesterol. SLOS can be associated with autism and other behavioral characteristics such as repeated self-injury, sensory hyper-reactivity, temperature dysregulation, and sleep disturbance [Tierney et al 2001, Tierney et al 2006]. Rates of autistic behavior reported in individuals with SLOS range from 50% to 86% [Manzi et al 2008]. One study found that three-fourths of the children with SLOS had ASD, about 50% diagnosed with autistic disorder and the rest with PDD-NOS [Sikora et al 2006]; no correlation was found between the abnormal metabolites and the presence or severity of autistic symptoms.

Other single gene disorders. Autism or autistic features have been described in children with many other single gene disorders. Most are associated with severe intellectual disability and significant dysmorphology and rarely are referred for medical evaluation with an initial question of autism. The list includes:

Moebius syndrome or sequence. Defined by unilateral or bilateral palsy of the sixth and seventh cranial nerves, Moebius syndrome is characterized by facial paralysis with inability to smile and fully abduct the eyes.It is often associated with abnormal tearing, seizures, hearing loss, and limb anomalies. About 30% of children with Moebius syndrome develop ASD [Johansson et al 2001, Stromland et al 2002, Bandim et al 2003]. A recent study confirmed the observations of Johansson et al [2001] that ASD occurs more frequently in individuals with Moebius syndrome with concurrent intellectual disability [Briegel et al 2009]. Presumably caused by an early disruption of embryonic blood supply leading to brain stem disruption, Moebius syndrome has been compared to thalidomide embryopathy which also damages the sixth and seventh cranial nerve and causes autism.

Landau-Kleffner syndrome (LKS). A small subset of children with ASD and late regression have LKS. These children develop sudden or gradual isolated language regression associated with seizures (epileptic aphasia) and/or severe EEG abnormality in deep sleep [Cortesi et al 2007]. In general, both the seizures and language impairment improve with normalization of EEG abnormalities [Spence & Schneider 2009].
Environmental Causes

The search for environmental causes of autism has been driven by the considerable increase in autism prevalence recorded over the last 20 years and the incomplete concordance for autism in monozygotic (MZ) twins.

In utero exposures, including valproic acid, thalidomide, and misoprostol (an abortifactant commonly used in South America) are recognized causes of autism. The Liverpool and Manchester Neurodevelopment Group recently reported a long-term study of 632 children exposed to antiepileptic drugs (AEDs) during gestation and found that children exposed to valproate in utero were seven times more likely to develop autism than those not exposed to AEDs. None of the families had a known family history of autism. They recommend that women taking valproate be informed of the risk for autism in children exposed during gestation [Bromley et al 2008].

Other factors that have been considered as causes of autism include expanded use of assisted reproductive technologies (ART) [Knoester et al 2007] and tocolytic drugs such terbutaline [Connors et al 2005].

Childhood immunizations given around the time that regressive-onset autism is recognized have been a focus of concern. Organic mercury, which constitutes roughly 50% of the preservative thimerosal used in certain injectable vaccines, and the measles-mumps-rubella (MMR) vaccine, which never contained mercury, have been studied. Though parental concern is still significant, multiple studies and lines of scientific evidence have identified no support for a relationship between immunizations and autism [DeStefano & Thompson 2004, Institute of Medicine 2004, Taylor 2006, Schechter & Grether 2008]. The original studies by Wakefield et al [1998] and Wakefield [1999] suggesting an associated between immunizations and autism have been disproved and the work was retracted by the journal The Lancet [Murch et al 2004]. One of the tragedies resulting from fear of an autism epidemic was the decreased use of childhood immunizations leading to out outbreaks of measles and childhood deaths [Jansen et al 2003, Offit 2008].
Multifactorial Inheritance

The more frequently affected sex (male) has a lower recurrence risk than the less frequently affected sex (female).
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The less often affected sex (female) is more severely affected than the more often affected sex (male).

Studies indicate that autism does not follow this model:

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Sibs of male and female probands with autism of unknown cause have the same risk of developing autism [Miles et al 2004].
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The proportion of relatives with a mild subclinical autism phenotype, defined as increased impulsivity, aloofness, shyness, over-sensitivity, irritability, eccentricity and anxiety, is not increased when the proband is female [Pickles et al 2000].
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When analyses are limited to probands with essential autism, females have less severe autistic symptoms than males [Miles et al 2004].

Lack of support for the classic multifactorial threshold model, however, does not eliminate the possibility that many genes are involved in autism. Instead, it suggests that genetic heterogeneity is the main impediment to understanding the inheritance of autism.
Genes that Cause or Increase the Risk of Autism

Determining specific genetic changes that increase the risk of developing autism is an area of intense study. The large-scale genetic studies of the last decade have ruled out the possibility that single gene of large affect causes a high proportion of autism. Rather it appears that a a significant number of highly penetrant autism alleles will be discovered in families. Study of these rare alleles will be essential to elucidating the pathogenetic mechanisms involved in the development of autism.

Array CGH has increased detection of copy number variants (CNVs) in autism and paved the way for identification of a number of new autism genes [Szatmari et al 2007]. Some CNVs may help identify highly penetrant causal mutations, while others may lead to the discovery of multiple common genetic variations which act in concert, possibly with environmental triggers to cause autism. Persuasive evidence for this common disease-common variant hypothesis in autism includes the presence of subtle sub-clinical autism symptoms in relatives of children with autism [Constantino et al 2009]. It is also probable that some CNVs may alter the expression of genes in the immediate vicinity of the CNV.

Table 1 which lists known and putative autism genes is unquestionably incomplete, as new candidate genes are being reported at an unprecedented rate. The genes are organized by pathogenesis to highlight the progress made in the functional assessment of autism candidate genes and pathways. In addition, some genes are included because of their compelling initial descriptionsthat still await confirmation. Selected references address both molecular and pathophysiologic descriptions.

SFARI gene is a new comprehensive, Web-based, searchable list of candidate genes associated with ASD. The candidate genes are richly annotated for their relevance to autism, along with an in-depth, up-to-date view of their molecular function extracted from the current scientific literature.

The Genetic Association Database provides online access to human genetic association studies performed on autism and other complex disorders.

Evaluation Stretegy

In addition to behavioral assessment to establish the diagnosis of autism and cognitive testing, the evaluation strategy for all individuals with autism includes a medical evaluation to identify medical issues that affect the development and behavior of nonverbal children and a clinical genetics evaluation to elucidate diagnostic possibilities. This basic evaluation should be expanded if the medical or family history and/or physical examination raise concerns about metabolic, medical, or neurologic conditions. Recent reports from the American Academy of Pediatrics [Johnson & Myers 2007] and the American College of Medical Genetics [Schaefer & Mendelsohn 2008] provide practical approaches to the evaluation of children with ASD.

Family history. A three-generation pedigree should be obtained with attention to behavioral and neurologic diagnoses. Relatives with behaviors that are possible manifestations of autism may be examined directly or their records reviewed. Language, social, and psychiatric disorders, including alcoholism and possibly other addictive disorders, occur more often in relatives, including sibs, of clearly autistic probands, particularly those with essential autism [Fombonne et al 1997a, Bolton et al 1998, Piven & Palmer 1999, Pickles et al 2000, Miles et al 2003].

Clinical examination. Physical examination should include the following:

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Measurement of height, weight, and occipital-frontal circumference (OFC) to identify (1) microcephaly or growth retardation which suggest various chromosome and monogenic syndromes, and (2) macrocephaly, which is present in approximately 35% of children with autism. In children with macrocephaly the molecularly defined macrocephaly syndromes that also cause autism, especially fragile X syndrome and PTEN hamartoma tumor syndrome, should be considered.
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Dysmorphology examination to look for developmental anomalies which date the onset of the disorder. An in depth dysmorphology examination by a medical geneticist provides the best data on which to base the diagnostic plan. In addition, the brief Autism Dysmorphology Measure has been developed for use by non-dysmorphologists who evaluate children with autism [Miles et al 2008].
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Laboratory testing. The following testing is recommended at the time of initial evaluation for all children with an ASD:

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Array comparative genomic hybridization (aCGH) has replaced high-resolution chromosome analysis as the test of choice for the evaluation of any child with an autism spectrum disorder. Note: Cytogenetic analysis, in addition to aCGH, is recommended when the family history suggests transmission of a balanced chromosome rearrangement.
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FMR1 molecular genetic testing for full mutations and premutations

The following should be considered based on the physical examination, review of systems, and family history:

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Electroencephalogram if clinical signs of seizures or developmental regression are present. The utility of obtaining EEGs routinely is debated. It is clear that a significant number of children have EEG abnormalities and the likelihood of observing an abnormality increases with the duration of the EEG.
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MRI. The brain MRI is indicated when the history and physical examination or neurologic examination suggests a localized lesion, tuberous sclerosis complex, Joubert syndrome, or an early environmental insult. Its routine use is controversial because of the expense and need for sedation or anesthesia by an anesthesiologist.
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Metabolic testing. Metabolic evaluation, including quantitative plasma amino acids; urine organic acids; purines, creatine and guanidinoacetate in urine; serum concentration of lactate, pyruvate, creatine kinase, and uric acid; and CBC is of limited benefit for the majority of individuals with autism. However, because diagnosing and treating a metabolic disorder can significantly alter prognosis, selective and targeted metabolic work-up is recommended based on history and physical examination. The evaluation should include review of the child’s newborn screening test results. Further studies are needed to determine the prevalence of mitochondrial respiratory chain disorders in autism, especially those with recurrent setbacks, hypotonia, and failure to thrive.
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Molecular genetic testing for a number of genes is clinically available and should be obtained if the phenotype and/or family history suggest the diagnosis

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Mode of Inheritance

Genetic counseling for families of probands with a chromosomal disorder, copy number variant, or a single gene disorder is based on information relevant to the primary diagnosis.

The mode of inheritance for autism of unknown cause is not known.
Risk to Family Members—Autism of Unknown Cause

Parents of a proband. No data on the risk to parents of a proband of having autism of unknown cause are available; however, parents of children with an ASD are more likely to exhibit mild autistic phenotypes, such as social awkwardness and a variety of psychiatric disorders including alcoholism, depression, obsessive-compulsive disorder, and panic and anxiety disorders when compared to parents of children with non-ASD disorders such as Down syndrome [Piven & Palmer 1999, Miles et al 2003, Wilcox et al 2003, Lauritsen et al 2005, Yirmiya & Shaked 2005]. In several studies rates of 10%-45% for social impairment, aloofness, shyness, and pragmatic language impairment were present in at least one parent of children with autism spectrum disorders [Freitag 2007]. Cederlund & Gillberg [2004] reported that 70% of probands with autism of unknown cause studied had a first- or second-degree relative with autistic symptoms, and that 15% had fathers with Asperger syndrome.

Sibs of a proband. The empiric aggregate risk to sibs of individuals with autism of unknown cause varies across studies but is generally considered to range from 5% to 10% for autism and 10% to 15% for milder symptoms, including language, social, and psychiatric disorders [Bolton et al 1994, Lauritsen et al 2005, Miles et al 2005, Landa 2008, Selkirk et al 2009]. For families with two or more affected children, the recurrence risk approaches 35% [Ritvo et al 1989]. No recurrence risk data are available for families who have one autistic child plus another child or relative with mild autistic symptoms. Therefore, the amount of weight to put on mild autistic symptoms in siblings, parents, and other relatives when estimating recurrence risk for families is unknown.

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Essential autism
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Male sibs (brothers) of a proband with essential autism have a 7% risk for autism and an additional 7% risk for milder autism spectrum symptoms [Miles et al 2005].
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Female sibs (sisters) of a proband with essential autism have a 1% risk for autism. The risk for milder autism spectrum disorder is unknown [Miles et al 2005].
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Complex autism. The recurrence risk to sibs of a proband with complex autism is 1% for autism and an additional 2% for milder autism spectrum symptoms [Miles et al 2005].

Offspring of a proband. No data are available.
Related Genetic Counseling Issues

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal testing for families at risk of having a child with a chromosomal disorder, copy number variant, or a single gene disorder known to be associated with autism may be available for the specific etiology; search the GeneTests Laboratory Directory for information on the specific syndrome to asses the availability of prenatal testing.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with autism, the following evaluations are recommended:

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Medical evaluation. A complete medical evaluation and review of systems to assess growth and identify health problems that may interfere with optimum development and progress. In particular, note:
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Sleep. Problems falling asleep, early or mid-night wakening and parasomnias are common. Routine sleep hygiene recommendations, search for underlying physical causes, and referral to sleep specialists are warranted. Medications should be delayed until underlying causes are ruled out.
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Gastrointestinal symptoms including both constipation and diarrhea are common in autism and respond to medical management. Referral to a gastroenterologist is recommended if symptoms are chronic
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Obesity. Children with autism are often treated with medications, such as atypical antipsychotics which can increase hunger and lead to weight gain. In addition, many children and teenagers are physically inactive, preferring the computer and video games.
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Cognitive testing. A cognitive assessment by a psychologist experienced in autism evaluations; however, since IQ scores may change especially in young children it is recommended that children be retested every three years. This is usually done through the school system and those records should be obtained.
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Language/communication assessment. Assess whether the child is functionally verbal or only has occasional words or echolalia. Language assessment by a trained speech/language pathologist with access to training modalities and communication modalities such as Picture Exchange Communication System (PECS). Even children who appear functionally verbal generally need ongoing speech and language therapy to gain skills in pragmatics and social and receptive communication.
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Family functioning, including financial resources including qualifications for Medicaid, Social Security Supplemental Income, and other state specific programs

Treatment of Manifestations

Optimally, an autism intervention program uses an experienced team of medical, behavioral, and educational specialists. Working with an established team is easiest for families; however, many physicians and families have successfully assembled programs that work well.

Early diagnosis and early intensive behavioral therapy are essential to an optimal outcome. Two comprehensive treatment reviews are Educating Children with Autism [Lord et al 2001] and Management of Children with Autism Spectrum Disorders from the American Academy of Pediatrics [Myers & Johnson 2007] are both available online. Also recommended is an evaluation of single-subject studies to determine which educational practices meet the criteria of "evidence-based practice" [Odom et al 2003].
Behavioral and Educational Therapy

Many interventions have been developed for children and youth with autism in the past 20 years. The effects of some of these interventions have been documented in peer-reviewed published research. Other interventions, although marketed to parents, have not been rigorously tested. The goal for practitioners is to prescribe and (as applicable) use scientifically based practices (SBP) when developing and implementing intervention plans. SBPs are those practices that have a substantial research base and are shown to be effective with children and youth with autism. Simpson [2005] provided a synthesis of autism intervention research and assigned classifications based on the level of empirical support. The classification categories are: scientifically based practice, promising practice, limited supporting information for practice, and not recommended. The interventions discussed below are considered either scientifically based or promising practices. The majority of interventions with empirical evidence of efficacy use structured behavioral and educational approaches to teach children to comprehend and use language, attend to their environment, imitate others, interact socially, and play appropriately with toys. Features include a functional approach to behavior problems and predictable and routine classroom and home arrangements with planned transitions between activities and environments.
Universal Support and Skill-Based Strategies

Environmental supports are changes to the environment that help the individual with ASD be more successful without requiring acquisition of new skills. Often these supports serve as a foundation for other targeted practices. These supports typically provide physical organization of the work space, task organization, clarity of transitions, and visual schedules/strategies.

The Treatment and Education of Autistic and related Communication-handicapped Children (TEACCH) program is a scientific-based example of a practice designed to increase students’ independence through physical and task organization [Mesibov et al 2004]. The intervention is designed to create environments (most typically classrooms and related learning settings) that provide clear expectations, structure, and predictability and reduce tendencies by children with ASD to over or under attend to stimuli through the use of physical structures. Work stations are created with clear task areas, break areas, task cues to provide support for sequencing of steps, materials and behavior expectations. Many materials and areas are color coded and supplemented with visuals, either written or pictorial. Although TEACCH procedures are more frequently used in school settings, many practitioners incorporate many of these structures into community and home environments (e.g., a bin of preferred items with visual play cues for children to use while mom is cooking). Another frequently used strategy is Visual Schedules which are designed to increase predictability and reduce anxiety. Visual representations of tasks or events, including their sequence, duration, temporal distance, cause and effect without an overall reliance on auditory processing is beneficial to learners with ASD [Mesibov & Howley 2003]. Visual strategies alone do not teach communication and should not be confused with promising formalized scientific practice strategies that use visual representations. See Communication in this section.

Applied Behavior Analysis (ABA) is an intervention based on the use of behavioral principles to change, reduce, or increase behaviors. It incorporates high levels of environmental support and uses them to target skill acquisition across multiple developmental domains. ABA has no age boundaries and teaches target behaviors coupled with specific processes for responses to increase (reinforce) or decrease behaviors. ABA programs are based on repeated analyses of an individual’s strengths related to environmental functioning [Alberto & Troutman 2008]. This approach is referred to as “functional analysis” and is an integral component of the federal laws that regulate the delivery of special education services [ILIAD 2004 (Individuals with Disabilities Education Act)]. Functional analysis seeks to identify the purpose for which an individual exhibits a maladaptive or prosocial behavior. This allows development of individualized and effective environmental supports and skill-based techniques to teach new behaviors. ABA, including functional analysis, is the intervention technique with the strongest research base supporting its effectiveness in both ASD and non-ASD populations.

A number of evidence-based or emerging practices, including Discrete Trial Teaching and Pivotal Response Training, are based on ABA principles. One such technique that is expected to emerge shortly as scientific is Incidental Teaching, which uses basic concepts of ABA in the child’s natural environment [McGee et al 1999, Peterson et al 2005].

Incidental Teaching is implemented around the child’s interests and typical activities, using natural supports such as favorite toys, people or foods as the basis for teaching new skills. To date, research has demonstrated success across all levels of cognitive and ASD symptomology, and most age ranges, especially in early childhood [McGee et al 1999]. Skills acquired through Incidental Teaching are considered more generalizable to day-to-day functioning when compared to methods like discrete trial training, which breaks down single tasks and teaches them separately [Lord et al 2001, Simpson et al 2005].

Cognitive Behavior Intervention, categorized as a promising practice for ASD, teaches problem solving schemas using systematic application of environmental supports, rules, and principles which lead to self-management and behavior regulation. It is anticipated as more research is being published that this strategy will soon be moved to scientific-based status for ASD. This practice is particularly helpful for teaching self-management skills and regulating one’s own behavior.

Sensory Integration (SI) is the organization and processing of sensory information for specific functional use. Proponents of sensory integration therapy view the aberrant behavior of children with autism as an attempt to establish an internal state of equilibrium. Scientific theory exists for this view, but little empiric data support its use. It is currently rated a promising practice by Simpson and colleagues based on a growing body of literature [Simpson et al 2005]. Despite a lack of specific data to support its use for ASD, caregivers at home and in the classroom report decreased hyperactivity, inattention, and self-stimulation following SI therapy. Although the program should be designed by an occupational therapist with training in sensory integration, many of the techniques, including brushing, use of weighted vests, swinging, and jumping are easily adapted to home and school use.

Communication. Communication impairment is one of the defining features of autism. Effective interventions to teach language and communication are also based on the principals of applied behavior analysis (ABA) and vary by the extent to which teaching is integrated into the child’s normal activities. At one end of the spectrum is discrete trial training that consists of intensive, rigidly structured, adult-directed, one-on-one interventions [Prizant et al 2000]. Debate exists about the appropriateness and ultimate success of teaching language skills outside of the contexts in which language is used. However, programs that use a discrete-trial training format are supported by published data and are rated as evidence-based practice [Heflin & Alaimo 2007]. Principles of ABA are also used in interventions in which instruction is embedded in home and classroom routines and the interaction is either shared or child directed. For example, Pivotal Response Training, Incidental Teaching, and the Picture Exchange Communication System are three naturalistic interventions considered to be scientifically based or a promising practice [Simpson 2005]. These naturalistic interventions can be used at school or home, and although the primary focus is language, they also target cognitive, play, and social communication skills.

Pivotal Response Training (PRT) [Koegel & Kern Koegel 2006], a scientifically based practice [Simpson et al 2005], was developed to teach skills and behaviors that enhance the child’s ability to learn and maintain new behaviors by natural consequences in typical environments. The main components of PRT are child choice, interspersing new tasks with those already mastered, reinforcing child attempts, gaining the child’s attention before giving directions, and teaching with multiple cues. PRT uses the child’s preferred activities and interests to provide motivation for learning new skills. Incidental teaching [Kaiser 2000], a promising practice [Simpson et al 2005] uses naturally occurring routines and activities, including play activities to encourage child initiations, particularly child requests. Adults reinforce the child’s language by providing access to requested activities or objects, modeling appropriate language and building turn-taking routines. Because language is taught in context, incidental teaching can be used to teach a variety of skills.

Picture Exchange Communication System (PECS) [Bondy et al 2004], a promising practice [Simpson et al 2005], was developed as a functional communication system for nonverbal children. With PECS, children use visual representations to request a desired object or activity. Children can also be taught to use the visual representations to comment on objects or activities of interest. Children progress through six phases of training that include exchanging a picture for an object or activity, making choices among pictures, and answering questions. Although not the original intent, many young children who use PECS do learn to talk.

Social. Individuals with autism experience social deficits that inhibit their ability to make and sustain friendships and navigate complex social environments. In social situations, these individuals generally lack the skills to initiate social interactions and fail to respond appropriately, leading to common descriptors such as socially awkward, self-centered, or inflexible. They also do not pick up nonverbal social cues and social prompts, and tend to display socially unacceptable behavior [Myles & Simpson 2002]. Without effective and targeted intervention, these deficits significantly affect long-term prognosis [Howlin & Karpf 2004].

Young children and those more affected by autism symptoms may benefit from play-oriented strategies, which are particularly effective for developing skills in turn-taking, sharing functional communication, and waiting, all of which are essential for effective social interactions. Play-based interventions such as Integrated Play Group and Milieu Teaching target individualized goals for the child and are distinct from ‘play therapy,’ which is often not effective for children with ASD, due in part to the emphasis of symbolic representation [Wolfberg 1999]. Learning Experiences: An Alternative Program for Preschoolers and Parents (LEAP) is a scientifically based intervention specifically focusing on social skills that generally takes place in a preschool setting but can also be implemented at home [Strain & Hoyson 2000].

Similar to the cognitive behavior interventions is a group of promising practices categorized as Social Decision Making Strategies [Simpson et al 2005]. These practices provide steps for making decisions, generating alternatives and understanding appropriate solutions in social situations. Examples include: social autopsies (deconstructing social situations that went wrong), stop-plot-go-so (determining the ‘who,’ ‘what,’ ‘when,’ ‘where,’ and ‘then what’ of social situations) and ‘stop,’ ‘observe,’ ‘deliberate,’ and ‘act’ (SODA) [Myles & Simpson 2003].

Another promising practice is Social Stories™, which is used to increase appropriate behavior and decrease problem behavior by explaining social situations in ways that are understandable to the student [Gray 2000]. The assumption is that problem behavior is caused by lack of understanding of what is expected or what is going to happen next; social stories build understanding, allowing the student to behave appropriately. Social stories are inexpensive to create and take much less time and expertise to implement than other interventions. Social Stories have been used successfully with children with ASD across a continuum of ages and abilities. Some variations are called Power Cards and Comic Scripts [Gagnon 2001].

Medical management. Although most children with autism are healthy, evidence is mounting that medical disorders have a significant effect on behaviors, level of functioning, and response to educational therapies. Sensory issues including a blunted pain response, inability to tell others when they are uncomfortable, and poor tolerance of medical evaluations can lead to suboptimal medical care. Emerging areas of research include gastrointestinal, feeding, sleep, metabolic, and pain disorders [Linday et al 2001, Bradley et al 2004, Polimeni et al 2005]. Evidence of gastroesophogeal reflux causing insomnia and self-injurious behaviors are compelling and indicate that physicians need to have a high index of suspicion, especially with unexplained behavioral exacerbations, and to provide the same level of medical intervention as in typically developing children. The Autism Treatment Network (ATN) is a consortium of 15 autism treatment center which was formed with support of Autism Speaks and the National Institutes of Health to develop a medically based approach to the diagnosis and treatment of individuals with autism. Algorithms for the initial assessment of children with autism as well as guidelines for continued medical care and surveillance are being developed and can be accessed through the Web site as well as through planned publications.

The use of medications has increased as newer medications, especially the atypical antipsychotics, which affect both the serotonin and dopamine systems, and serotonin reuptake inhibitors (SRIs), which modulate the serotonin system, have been studied in children. In 1997, the National Institute of Mental Health formed the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network to investigate the safety and efficacy of drugs for treating the behaviors associated with autism. Reports from that consortium have provided authoritative reviews of the pharmacotherapy of autism [McDougle et al 2005, Posey et al 2008]. The conclusions:

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No medications are autism specific. Medications should be selected to ameliorate a specific symptom such as aggressive or self-injurious behavior, agitation, anxiety, poor sleep and repetitive or stereotypic behaviors that interfere with learning and social interactions [Bodfish 2004, McDougle et al 2005].
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A medication that alleviates one maladaptive behavior, such as aggression or hyperactivity, may have no effect on core autistic symptoms.
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Marked differences exist in the efficacy and side effects of drugs in adults vs children.
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Individual antipsychotic medications within the same class may differ with respect to their potency and side effect profile.
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Affected individuals may respond differently to the same medication. The response to a medication may reflect genetic differences between individuals, the waxing and waning of the behaviors over time, the progression of the disorder, and/or placebo effect.
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Medication management should be integrated into a family centered, multi-modal behavioral and educational program.

In the treatment of the catatonia syndrome, antipsychotic medications are contraindicated and treatment with benzodiazepines and electroconvulsive therapy has been helpful [Wing & Shah 2000, Billstedt et al 2005, Kakooza-Mwesige et al 2008].

Alternative therapies. Complementary and alternative medical (CAM) treatments are commonly used for children with autism [Hanson et al 2007]. Levy & Hyman [2008] reviewed the evidence supporting the most frequently used treatments, including categories of mind-body medicine, energy medicine, and biologically based, manipulative, and body-based practices. Clinical providers need to understand the evidence for efficacy (or lack thereof) and potential side effects.

Though parents generally consider CAM practices a safe alternative to prescribed medications, most treatments have not been adequately studied and do not have evidence to support their use. Some CAM practices, such as administration of secretin, facilitated communication, auditory training, have evidence to reject their use. A few CAM practices such as administration of melatonin have emerging evidence to support their use.
Surveillance

Children with autism should be followed at least annually to monitor health, educational, language, and behavioral progress. An update of the areas covered in the initial evaluation is recommended. Identification of specific complications is a targeted goal of the Autism Treatment Network, which will be following a large cohort of individuals into adulthood. Since diagnostic and treatment recommendations will continue to be revised, periodic diagnostic reappraisals by a medical geneticist or an autism center are recommended. As more individuals receive etiologic diagnoses, diagnosis-specific surveillance profiles will be developed.

Complications for which evidence supports routine monitoring include:

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Seizures
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Sleep disturbances
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Feeding problems
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Gastrointestinal symptoms
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Medication-specific side effects
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Mood and psychiatric dysfunction
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Medication-induced complications. All children on medications should be closely monitored for medication side effects.

Agents/Circumstances to Avoid

A hands-off or wait-and-see approach should be avoided because children with autism are unlikely to be able to navigate the social world and develop reciprocal communication skills without intensive therapeutic intervention.

Families need to be cautioned about unproven and potentially dangerous “alternative therapies” that may be promoted either by well-meaning but naïve people or by unscrupulous groups, individuals, or clinics.
Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Resources

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page link.
Literature Cited

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